CN1270713C - Synergistic pharmaceutical combination for prevention or treatment of diabetes - Google Patents
Synergistic pharmaceutical combination for prevention or treatment of diabetes Download PDFInfo
- Publication number
- CN1270713C CN1270713C CNB02814340XA CN02814340A CN1270713C CN 1270713 C CN1270713 C CN 1270713C CN B02814340X A CNB02814340X A CN B02814340XA CN 02814340 A CN02814340 A CN 02814340A CN 1270713 C CN1270713 C CN 1270713C
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- China
- Prior art keywords
- addition salts
- acid
- pharmaceutical composition
- diabetes
- medicinal suitable
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 18
- 230000002195 synergetic effect Effects 0.000 title claims abstract description 9
- 230000002265 prevention Effects 0.000 title claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 230000003178 anti-diabetic effect Effects 0.000 claims abstract description 22
- 239000012050 conventional carrier Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 44
- -1 nicotinoyl Chemical group 0.000 claims description 39
- 230000003213 activating effect Effects 0.000 claims description 35
- 230000000694 effects Effects 0.000 claims description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 12
- 206010022489 Insulin Resistance Diseases 0.000 claims description 11
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- 229960003105 metformin Drugs 0.000 claims description 9
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- 239000003513 alkali Substances 0.000 claims description 8
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 7
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 7
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 7
- 208000001280 Prediabetic State Diseases 0.000 claims description 7
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 7
- 208000011580 syndromic disease Diseases 0.000 claims description 7
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- 230000001575 pathological effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 210000002824 peroxisome Anatomy 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 150000003053 piperidines Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical group 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention refers to a synergistic pharmaceutical combination which comprises (a) a first pharmaceutical composition containing an antidiabetic or anti-hyperlipidemic active agent and one or more conventional carrier(s), and (b) a second pharmaceutical composition containing a hydroximic acid derivative of the formula I and one or more conventional carrier(s). The pharmaceutical combination is suitable for the prevention or treatment of , among others, diabetes mellitus.
Description
The present invention relates to a kind of be applicable to prevention or treatment prediabetes state, metabolism X-syndrome or diabetes and with the relevant disorder of top listed state, i.e. endogenous metabolism disorder, insulin resistance, dyslipidemia, alopecia, alopecia generalisata and/or based on the synergistic pharmaceutical combination of the female incretion disorder that produces the masculine sex character advantage.
In industrially developed country, increasing people suffers from diabetes.For example, because of producing and using the defective of insulin to promote type 2 diabetes mellitus (to be noninsulindependent diabetes, NIDDM) to occur.The h and E factor has caused the formation of the serious disease of this extensive distribution comparably, and is accompanied by significant mortality rate.In fact, only obtain the treatment that alleviates with the patient of insulin or another anti-diabetic or the treatment of lipidemia medicine, it has improved quality of life, yet occurs the complication that diabetes are followed inevitably.
The purpose of this invention is to provide a kind of pharmaceutical composition, it is applicable to the generation of prevent diabetes or the complication followed of diabetes at least, perhaps, if this prevention no longer may the time, be used for effectively treating described complication.
Find that above-mentioned purpose is to realize by a kind of synergistic pharmaceutical combination of following compositions that comprises:
(a) first pharmaceutical composition, it contain a kind of anti-diabetic or lipidemia activating agent and one or more conventional carriers and
(b) second pharmaceutical composition, it contains hydroxamic acid derivatives or its medicinal suitable acid-addition salts and one or more conventional carriers of following formula,
Wherein
R
1Represent hydrogen atom or C
1-5Alkyl,
R
2Represent hydrogen atom, C
1-5Alkyl, C
3-8Cycloalkyl or optional by the phenyl of hydroxyl or phenyl replacement, perhaps
R
1And R
2Form 5-to 8-unit ring with the nitrogen-atoms that links to each other with them, optional one or more other nitrogen, oxygen or the sulphur atom of containing of these rings, and described ring can encircle or the heterocycle condensation with another aliphatic series, described another encircles preferred phenyl ring, naphthalene nucleus, quinoline ring, isoquinolin ring, pyridine ring or pyrazoline ring, and optional described nitrogen and/or sulfur heteroatom exist with the form of oxide or dioxide
R
3Represent hydrogen atom, phenyl, naphthyl or pyridine radicals, wherein said group can be by one or more halogen atoms or C
1-4Alkoxyl replaces,
Y is hydrogen atom, hydroxyl, optional by the amino C that replaces
1-24Alkoxyl, contain the C of the two keys of 1-6
2-24Polyalkenes oxygen base, C
1-25Alkanoyl, C
3-9Alkenoyl (alkenoyl) or R
7The group of-COO-, wherein R
7Representative contains the C of 1-6 two keys
2-30Polyalkenyl,
X represents halogen atom, amino, C
1-4Alkoxyl or
X and B form an oxygen atom, perhaps
X and Y with and their carbon atoms of linking to each other and between described carbon atom-NR-O-CH
2-group forms the ring of following formula together
Wherein
Z represention oxygen atom or formula-N=or-group of NH-,
R represent hydrogen atom or
R and B form a chemical bond,
A is C
1-4The group of alkylidene or a chemical bond or following formula:
Wherein
R
4Represent hydrogen atom, C
1-5Alkyl, C
3-8Cycloalkyl or optional by halogen atom, C
1-4Alkoxyl or C
1-5The phenyl that alkyl replaces,
R
5Represent hydrogen atom, C
1-4Alkyl or phenyl,
M has value 0,1 or 2,
N has value 0,1 or 2.
The present invention strengthens the understanding of the sensitivity of insulin based on the hydroxamic acid derivatives of formula I.Therefore, in the presence of the medicinal suitable acid-addition salts of the hydroxamic acid derivatives that formula I is arranged or its, be used for the treatment of the anti-diabetic of this pathological state or dosage that the lipidemia activating agent can be quite low and obtained target effect, reduce thus or eliminated the side effect that traditional treatment is followed.
From United States Patent (USP) 4,308,399 and EP 417 210 learn the hydroxamic acid derivatives of formula I.According to these documents, these chemical compounds can be used for treating diabetic angiopathy, and a part has selectivity β-barrier effect in the middle of them.
According to the Hungarian patent application of announcing with code T/66350 number 2385/92, some hydroxamic acid derivatives in the formula I scope can be used for treating the vascular complication that causes because of diabetes.
Various other biological effects of the hydroxamic acid derivatives of formula I also are known, wherein especially it is used to prevent and treat the disease (WO 97/13504) in mitochondrion source, be used to strengthen the stress protein matter level (WO 97/16439) of cell, be used to postpone skin aging process (WO 97/23198), anti-autoimmune disease (WO 00/07580) etc.
The definition of used term in description and claims:
Pharmaceutical composition is the combination of two kinds of medical active agent, wherein
1) use the pharmaceutical methods of one or more conventional carriers and any conventional that each activating agent is converted into independent pharmaceutical composition one by one, and gained two class pharmaceutical compositions give the patient simultaneously or give one of them earlier in this case, give another again behind the certain hour at interval;
2) or two kinds of activating agents changed into single pharmaceutical composition, said composition can be needed its patient.Under one situation of back, pharmaceutical composition can contain the mixture of two kinds of activating agents or the different parts that each activating agent may reside in pharmaceutical composition, and for example their one are at the tablet core core, and another is in the coating of tablet core core.Certainly, use the pharmaceutical methods of one or more conventional carriers and any conventional to prepare this single medicine compositions.
The anti-diabetic activity agent is meant any medical active agent that is usually used in treating diabetes.They mainly are following materials:
-insulin,
-insulin-sensitizing activity agent (Sensitizing active agent),
The activating agent that-raising insulin produces,
-sulfonamides,
-Biguanide derivative and
-Alpha-glucosidase inhibitor.
As insulin, at first, use the insulin human that makes by recombinant technique, in general with it through parenterai administration.
The insulin-sensitizing activity agent improves the effect of insulin.Most important type is PPAR (peroxisome multiplication agent-activated receptor) γ-agonist in the middle of them, thiazolidine diketone derivative for example, such as pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridine radicals) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione], troglitazone [(±)-5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group]-phenyl] methyl]-2,4-thiazolidinedione], ciglitazone [the 5-[[4-[(1-methylcyclohexyl) methoxyl group] phenyl] methyl]-2, the 4-thiazolidinedione, rosiglitazone (rosiglitazone) [(±)-5-[4-[2-[N-methyl-N-(2-pyridine radicals) amino]-ethyoxyl] benzyl]-2, the 4-thiazolidinedione] and other 2,4-thiazolidine diketone derivative and medicinal suitable acid-addition salts thereof.
The activating agent that improves the insulin generation is as follows: Mi Gelie naphthalene (mitiglinide) [(α S, 3 α R, 7aS)-octahydro-γ-oxo-α-(phenyl methyl)-2H-iso-indoles-2-butanoic acid], repaglinide [(S)-2-ethyoxyl-4-[2-[[3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] amino]-the 2-oxoethyl] benzoic acid], Si Gelienai (senaglinide) (being nateglinide) [N-[[(anti--4-(1-Methylethyl)-cyclohexyl] carbonyl]-the D-phenylalanine] or medicinal suitable acid-addition salts or its medicinal suitable salt.
In the sulfonamides; the most important thing is sulfonyl urea derivates; tolbutamide [N-[(butyl amino)-carbonyl]-4-methyl benzenesulfonamide for example]; chlorpropamide [4-chloro-N-[(propyl group amino) carbonyl] benzsulfamide]; tolazamide [N-[[(hexahydro-1 H-azepines-1-yl) amino] carbonyl]-the 4-methyl benzenesulfonamide]; acetohexamide [4-acetyl group-N-[(cyclohexyl amino) carbonyl] benzsulfamide] or the like as first generation sulfonylurea; perhaps glibenclamide [5-chloro-N-[2-[4-[[[(cyclohexyl amino) carbonyl] amino for example] sulfonyl] phenyl] ethyl]-the 2-methoxy benzamide]; glipizide [N-[2-[4-[[[(cyclohexyl amino) carbonyl] amino] sulfonyl] phenyl] ethyl]-5-methylpyrazine Methanamide]; gliclazide [N-[[(six hydrogen ring penta [c] pyrroles-2 (1H)-yl) amino] carbonyl]-the 4-methyl benzenesulfonamide]; glimepiride is [anti--3-ethyl-2; 5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl) amino] carbonyl] amino] sulfonyl] phenyl] ethyl]-2-oxo-1H-pyrroles-1-Methanamide]; gliquidone [N-[(cyclohexyl-amino) carbonyl]-4-[2-(3; 4-dihydro-7-methoxyl group-4; 4-dimethyl-1; 3-dioxo-2 (1H)-isoquinolyl) ethyl] benzsulfamide]; glibornuride [N-[[(3-hydroxyl-4; 7; 7-trimethyl dicyclo [2.2.1] heptan-2-yl) amino] carbonyl]-the 4-methyl benzenesulfonamide]; glisoxepide [N-[2-[4-[[[[(hexahydro-1 H-azepines-1-yl) amino] carbonyl] amino]-sulfonyl] phenyl] ethyl]-5-methyl-3-Isoxazolecarboxamidederivatives]; glibenclamide [5-chloro-N-[2-[4-[[[(cyclohexyl amino) carbonyl]-amino] sulfonyl] phenyl] ethyl]-the 2-methoxy benzamide]; Glisentide [N-[2-[4-[[[(cyclopenta amino) carbonyl] amino] sulfonyl] phenyl] ethyl]-the 2-methoxy benzamide]; glisolamide [N-[2-[4[[[(cyclohexyl amino) carbonyl] amino] sulfonyl] phenyl] ethyl]-5-methyl-3-Isoxazolecarboxamidederivatives]; [N-[5-(1 for glybuzole; the 1-dimethyl ethyl)-1; 3,4-thiadiazoles-2-yl] benzsulfamide]; glyclopyramide [4-chloro-N-[(1-pyrrolidinyl amino) carbonyl] benzsulfamide] or the like as second filial generation sulfonylurea and medicinal suitable acid-addition salts thereof.
Most important Biguanide derivative can characterize by following formula:
Wherein
R
8, R
9, R
10And R
11Represent hydrogen atom, C independently
1-10Alkyl, naphthyl, phenyl or phenyl (C
1-4Alkyl) group, wherein in front under two kinds of situations phenyl optional by 1-3 substituent group replacement, these substituent groups can be halogen atom, C independently
1-4Alkyl or C
1-4Alkoxyl, condition are R
8, R
9, R
10And R
11One of be not hydrogen atom, perhaps
R
8And R
9With adjacent nitrogen atom and/or R
10And R
11Form a 5-or 6-unit, saturated, unsaturated or aromatic ring with adjacent nitrogen atom, these rings can with another 5-or 6-unit be saturated, unsaturated or aromatic ring (optional also contain a nitrogen-atoms) condenses.
Particularly preferred Biguanide derivative is metformin [N, N-dimethylimino auxotox radical diamides], buformin [N-butyl imino-diacetic carbon imino-diacetic amide] and phenformin [N-(2-phenylethyl) imino-diacetic carbon imino-diacetic amide].
Alpha-glucosidase inhibitor inhibitory enzyme alpha-Glucosidase.Its important representative is a miglitol [1 for example, 5-dideoxy-1, the 5-[(2-hydroxyethyl) imino group]-the D-glucitol], acarbose [O-4,6-dideoxy-4-[[[1S-(1 α, 4 α, 5 β, 6 α)]-4,5,6-trihydroxy-(3-hydroxymethyl)-2-cyclohexene-1-yl] amino]-α-D-glucopyranosyl-(1 → 4)-O-α-D-glucopyranosyl-(1 → 4)-D-glucose], voglibose [3,4-dideoxy-4-[[2-hydroxyl-1-(hydroxymethyl) ethyl] amino]-2-C-(hydroxymethyl)-D-epi-inositol] or the like.
The lipidemia activating agent is meant any medical active agent that is usually used in treating the hyperlipidemia level.They are to be categorized into following chemical compound:
The aryloxy group alkane acid derivative,
HMG coenzyme reductase inhibitor,
Nicotinic acid derivates,
The antacid that is used for bile acid.
In the aryloxy group alkane acid derivative, preferred activating agent is chlorine Bei Te [2-(4-chlorophenoxy)-2-methyl-ethyl propionate] for example, [5-(2 for gemfibrozil, 5-dimethyl-phenoxy group)-2,2-dimethyl valeric acid], simfibrate [2-(4-chloro-phenoxy group)-2 Methylpropionic acid 1,3-propylene diester], etofibrate [3-pyridine carboxylic acid 2-[2-(4-chlorophenoxy)-2-methyl isophthalic acid-oxopropoxy] ethyl ester], ciprofibrate [2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid], Ronifibrate [3-pyridine carboxylic acid 3-[2-(4-chlorophenoxy)-2-methyl isophthalic acid-oxopropoxy] propyl ester] or the like.
In HMG coenzyme reductase inhibitor, most important activating agent is as follows: lovastatin [[1S-[1 α (R*), 3 α, 7 β, 8 β (2S*, 4S*), 8 α β]]-2-Methyl Butyric Acid 1,2,3,7,8,8 α-six hydrogen-3,7-dimethyl-8-[2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl]-1-naphthalene ester], fluvastatin [[R*, S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methyl-ethyl)-1H-indole-2-yl]-3,5-dihydroxy-6-enanthic acid], pravastatin [[1S-[1 α (β S*, δ S*), 2 α, 6 α, 8 β (R*), 8a α]]-1,2,6,7,8,8a-six hydrogen-β, δ, 6-trihydroxy-2-methyl-8-(2-methyl isophthalic acid-oxo butoxy)-1-naphthalene enanthic acid one sodium salt], simvastatin [[1S-[1 α, 3 α, 7 β, and 8 β (2S*, 4S*), 8 α β]]-2,2-acid dimethyl 1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-[2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl]-1-naphthalene ester], atorvastatin [[R-(R*, R*)]-and 2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-enanthic acid] or the like.
In nicotinic acid derivates, below for example using: acipimox [5-methylpyrazine formic acid 4-oxide], niceritrol [3-pyridine carboxylic acid 2, two [[(the 3-pyridine radicals carbonyl) oxygen base] methyl]-1 of 2-, the 3-propylene diester], nicomol [3-pyridine carboxylic acid (2-hydroxyl-1,3-hexamethylene two subunits)-four (methylene) ester], nicoclonate [3-pyridine carboxylic acid 1-(4-chlorphenyl)-2-methyl propyl ester] or the like.
In the antacid of conjugated bile acid, importantly as follows: colestipol [a kind of basic anion exchange resin: have N-(2-the amino-ethyl)-N ' of (chloromethyl) oxirane-[2-[(2-amino-ethyl) amino]-ethyl]-1,2-ethylenediamine polymer], colestyramine [a kind of synthetic strong-base anion-exchange resin, contain the quaternary ammonium functional group that links to each other with styrene diethylene benzene copoly mer], polidexide[anion exchange resin, contain quaternary ammonium group in conjunction with the enteral bile acid] or the like.
Anti-diabetic and lipidemia activating agent can be recognized from document.If desired and chemically if possible, the form that these activating agents can its medicinal suitable acid-addition salts or use with the form of the salt that forms with medicinal suitable alkali.
In this description and claims, C
1-4Alkyl is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group or isobutyl group.
Except top listed, C
1-5Alkyl can also be a n-pentyl for example.
C
1-4Alkoxyl for example can be methoxyl group, ethyoxyl, positive propoxy or n-butoxy.
Halogen atom for example is fluorine, chlorine, bromine or iodine atom.
C
3-8Cycloalkyl is for example represented cyclopropyl, cyclopenta, cyclohexyl, suberyl or ring octyl group.
Containing nitrogen-atoms and can containing the first ring of another heteroatomic 5-to 8-for example is pyrroles, pyrazoles, imidazoles, oxazole, thiazole, pyridine, pyridazine, pyrimidine, piperazine, morpholine, indole, quinoline ring or the like.
Except top listed alkoxyl, C
1-24Alkoxyl can also be for example n-pentyloxy, the last of the ten Heavenly stems oxygen base, dodecyl oxygen base, octadecyl oxygen base etc.
C
1-25Alkanoyl for example is formoxyl, acetyl group, propiono, bytyry, caproyl, palmityl, stearyl etc.
C
3-9Alkenoyl for example is acryloyl group, pentenoyl, hexenoyl, heptene acyl group, octene acyl group etc.
When Y represents formula R
1During the group of-COO-, it for example can be Caulis et Folium Lini acyl group, inferior oleoyl, two dodecahexaene acyl groups, eicosapentaenoic acyl group, arachidonic acyl group etc.
Work as R
3When representing pyridine radicals, if necessary, its nitrogen-atoms can be the form of N-oxide.Equally, work as R
1And R
2When forming 5-to 8-unit ring with adjacent nitrogen atom, piperidines basic ring for example, if necessary, the form that its nitrogen-atoms also can the N-oxide exists.
Medicinal suitable acid-addition salts is meant and medicinal suitable mineral acid example hydrochloric acid or sulphuric acid etc., perhaps the acid-addition salts that forms with medicinal appropriate organic such as acetic acid, fumaric acid, lactic acid etc.
When anti-diabetic or lipidemia activating agent have can be with the salifiable chemical constitution of alkali shape the time, also can use the salt of the activating agent that forms with medicinal suitable inorganic or organic base.When described activating agent can form acid-addition salts with acid, also can use the medicinal suitable acid-addition salts of this activating agent.
In the hydroxamic acid derivatives of formula I, preferred subclass is made up of the hydroxamic acid derivatives and the medicinal suitable acid-addition salts thereof of following formula
R wherein
1, R
2, R
3, R
4, R
5, m is identical with the definition among the formula I with n, X represents halogen atom or amino, the Y representation hydroxy.
Hydroxamic acid derivatives and medicinal suitable acid-addition salts, the wherein R of special preferred formula II
1And R
2Form piperidino with adjacent nitrogen atom, R
3Be pyridine radicals, m and n are 0, and X defines as above.Wherein, preferred especially O-(3-piperidino-2-hydroxyl-1-propyl group) nicotinoyl amidoxim (nicotinic amidoxime) and medicinal suitable acid-addition salts, preferred especially one hydrochlorate or dihydrochloride.
Another favourable subclass of the hydroxamic acid derivatives of formula I is made up of the chemical compound and the medicinal suitable acid-addition salts thereof of following formula
R wherein
1, R
2, R
3Identical with among A definition and the formula I.
The preferred subclass of another of the hydroxamic acid derivatives of formula I is made up of the cyclic compound and the medicinal suitable acid-addition salts thereof of following formula
R wherein
1, R
2, R
3Identical with among A definition and the formula I, Z represention oxygen atom or formula-N=or-group of NH-.
The further preferred subclass of the hydroxamic acid derivatives of formula I is made up of the chemical compound and the medicinal suitable acid-addition salts thereof of following formula
R wherein
1, R
2, R
3Identical with among A definition and the formula I, R
6Represent C
1-4Alkyl.
The chemical compound of formula I can use from United States Patent (USP) 4,308, and 399, EP 417 210 and the known method of Hungarian patent application publication number T/66350 make.
In synergistic pharmaceutical combination of the present invention, (a) quality (or weight) of the medicinal suitable acid-addition salts of the hydroxamic acid derivatives of its medicinal suitable acid-addition salts of anti-diabetic or lipidemia activating agent or (if desired with chemistry if possible) or the salt that forms with medicinal suitable alkali and (b) formula I or its is than normally (1-100): (100-1).One or both pharmaceutical compositions of this medicinal combination are fit to per os or parenterai administration and are solid or fluid composition.Proper dosage form and processing thereof and useful carrier can learn from document, Remington ' s Pharmaceutical Sciences for example, Mack Publishing Co., Easton, USA.
Preferably, synergistic pharmaceutical combination of the present invention comprises the medicinal suitable acid-addition salts of the hydroxamic acid derivatives of (a) formula II or its and (b) its medicinal suitable acid-addition salts of anti-diabetic or lipidemia activating agent or (if desired with chemistry if possible) or the salt that forms with medicinal suitable alkali, and wherein these activating agents are present in other pharmaceutical composition of branch or are present in the single conventional medicine compositions.This anti-diabetic or lipidemia activating agent for example can be one of top listed materials.Therefore, preferred synergistic pharmaceutical combination of the present invention can contain the hydroxamic acid derivatives of (a) formula II, for example O-(3-piperidino-2-hydroxyl-1-propyl group) nicotinoyl amidoxim or its medicinal suitable acid-addition salts such as dihydrochloride or a hydrochlorate and (b
1) anti-diabetic activity agent such as insulin, or insulin-sensitizing activity agent such as thiazolidine diketone derivative, pioglitazone for example, troglitazone, ciglitazone, rosiglitazone, or the activating agent such as the Mitiglinide of the generation of raising insulin, repaglinide, Si Gelienai, or a kind of sulfanilamide such as tolbutamide, chlorpropamide, tolazamide, acetohexamide, glibenclamide, glipizide, gliclazide, glimepiride, gliquidone, glibornuride, glisoxepide, glibenclamide, Glisentide, glisolamide, glybuzole, glyclopyramide, or the Biguanide derivative of formula VI, preferred metformin, buformin, phenformin, or Alpha-glucosidase inhibitor such as miglitol, acarbose or voglibose, or (b
2) lipidemia activating agent such as aryloxy group alkane acid derivative, such as chlorine Bei Te, gemfibrozil, simfibrate, etofibrate, ciprofibrate, Ronifibrate or HMG coenzyme reductase inhibitor, such as lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin or nicotinic acid derivates, such as the antacid of acipimox, niceritrol, nicomol, nicoclonate or bile acid, such as colestipol, colestyramine, polidexide or (if desired with chemistry if possible) its medicinal suitable acid-addition salts or with (b
1) and (b
2) salt that forms of the medicinal suitable alkali of the material that provides.
Another preferred pharmaceutical compositions of the present invention comprises chemical compound or its medicinal suitable acid-addition salts and the (b of (a) formula III, IV or V
1) anti-diabetic activity agent such as insulin, or insulin-sensitizing activity agent such as thiazolidine diketone derivative, pioglitazone for example, troglitazone, ciglitazone, rosiglitazone, or the activating agent such as the Mitiglinide of raising insulin production, repaglinide, Si Gelienai, or sulfanilamide such as tolbutamide, chlorpropamide, tolazamide, acetohexamide, glibenclamide, glipizide, gliclazide, glimepiride, gliquidone, glibornuride, glisoxepide, glibenclamide, Glisentide, glisolamide, glybuzole, glyclopyramide, or the Biguanide derivative of formula VI, preferred metformin, buformin, phenformin, or Alpha-glucosidase inhibitor such as miglitol, acarbose or voglibose, or (b
2) the lipidemia activating agent, for example aryloxy group alkane acid derivative such as chlorine Bei Te, gemfibrozil, simfibrate, etofibrate, ciprofibrate, Ronifibrate, or HMG coenzyme reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, or nicotinic acid derivates such as acipimox, niceritrol, nicomol, nicoclonate, or the antacid of bile acid such as colestipol, colestyramine, polidexide or (if desired with chemistry if possible) its medicinal suitable acid-addition salts or with (b
1) and (b
2) salt that forms with medicinal suitable alkali that provides.
Use of the influence of following experimental study compositions of the present invention to glucose-sensitive.All tests of carrying out meet European Community's guideline of nursing and service test animal.
The New Zealand white rabbit of growing up, heavy 3-3.2kg, stable breeding is in animal housing's (little time of one day 12-/dark cycle, temperature is 22-25 ℃, and relative humidity is 50-70%), an animal is arranged in each fence, arbitrarily feed is purchased laboratory feedstuff and tap water, uses these animals from start to finish.These animals undergo surgery after adapting to for two weeks.
Under aseptic condition, undergo surgery.With the 10mg/kg diazepam (Sigma, St.Louis, MO, USA) (intravenous heavy dose Hungary) is injected rabbit anesthesia for EGIS Pharmaceuticals Ltd., Budapest with the 5mg/kg ketamine.As people such as Szilvassy Z., Br.J.Pharmacol.,
112, 999-1001 (1994) is described, subcutaneously gives lignocaine (EGISPharmaceuticals Ltd., Budapest is Hungary) to alleviate local pain.Polyethylene catheter is inserted in two main arms of jugular vein and left neck artery.These conduits are external through nape.It is open to fill heparin sodium aqua (100lU/ml) that these pipelines keep.
The research of hyperinsulinemia euglycaemic Fructus Vitis viniferae sugar tongs
(13mU/kg, NOVONordisk Copenhagen) inject people's insulin regular with constant rate of speed through one of these duct of Arantius in 120 minutes.This insulin injects the plasma insulin immunoreactivity that produces 100 ± 5 μ U/ml with steady statue.This value is equivalent to 5 times of upper limits of normal value.Take out blood sample (0.3ml) from arterial at interval with 10 minutes and be used for blood glucose concentration.By variable glucose injection rate blood glucose concentration is kept constant (5.5 ± 0.5mmol/l) through second duct of Arantius.When blood-glucose was stablized at least 30 minutes, we define this condition was steady statue.Under this steady statue, took out other blood sample (0.5ml) with plasma insulin at interval with 10 minutes.With the glucose injection rate (mg/kg/min) during the steady statue be used to characterize insulin sensitivity [people such as DeFronzo R.A., Am.J.OfPhysio.,
237, E214-223 (1979)].With test-compound respectively per os give healthy and hypercholesteremic animal every day with single dose, continue 5 days, and in each test group of forming by 6 animals that the glucose injection rate of the 6th day mensuration is average.Use one group of health and one group of hypercholesteremic animal in contrast.The gained result is presented in table 1 and 2.
Table 1
Insulin sensitivity by the sign of the glucose injection rate (mg/kg/min) during the steady statue
The property
| Animal groups | Contrast | BGP-15 30mg/kg dosage every day p.o. | Metformin 100mg/kg dosage every day p.o. | BGP-15 (30mg/kg)+metformin (100mg/kg) |
| Normal HC | 14.6±1.03 9.7±1.0 | 15.9+1.82 13.4+1.11 | 15.8±0.83 11.7±0.87 | 18.1+0.92 15.8+0.75 |
Normally=healthy animal is used for this test;
HC=is used for this test with the hypercholesteremia animal;
BGP-15=O-(3-piperidino-2-hydroxyl-1-propyl group) nicotinoyl amidoxim hydrochlorate.
Table 2
Insulin sensitivity by the sign of the glucose injection rate (mg/kg/min) during the steady statue
The property
| Animal groups | Contrast | BGP-15 30mg/kg dosage every day p.o. | Troglitazone 75mg/kg dosage every day p.o. | BGP-15 (30mg/kg)+troglitazone (75mg/kg) |
| Normal HC | 13.9+1.22 9.0+0.84 | 15.4+1.26 13.8+1.29 | 14.3±0.08 14.1±1.33 | 16.9+1.04 16.07+0.84 |
Normally=healthy animal is used for this test;
HC=is used for this test with the hypercholesteremia animal;
BGP-15=O-(3-piperidino-2-hydroxyl-1-propyl group) nicotinoyl amidoxim hydrochlorate.
In fact, measured the amount that obtains the glucose that constant blood glucose levels injects in the superincumbent test.Glucose in requisition for higher amount under the given blood glucose levels that indication insulin effect improves is favourable.Therefore, the glucose injection rate of mensuration is high more, and the efficient that test-compound obtains is high more.
As what see in the table 1, the value that obtains in healthy animal is than the value height of hypercholesteremia animal certainly.In matched group, glucose injection rate low than in the group of handling with BGP-15 or metformin.In a word, in healthy and cholesteremia animal, when animal is handled with BGP-15 and metformin, obviously than the glucose injection rate height that only gives a kind of test-compound.Therefore, observe synergism between BGP-15 and the metformin.
As shown in table 2, identical with the situation of BGP-15 and troglitazone.
The present invention also comprises a kind of treatment or prevention prediabetes state, the method of metabolism X-syndrome or diabetes and the disorder relevant with last surface state, these disorders are the endogenous metabolism disorder, insulin resistance, dyslipidemia and/or to produce the female incretion disorder of masculine sex character advantage, wherein suffer from or indicate shown in state the patient on the one hand with the treatment effective dose anti-diabetic or antilipemic activating agent, perhaps (if desired with chemistry if possible) its medicinal suitable acid-addition salts or the salts for treating that forms with medicinal suitable alkali, on the other hand, treat with hydroxamic acid derivatives or its medicinal suitable acid-addition salts of formula I.
The hydroxamic acid derivatives of this anti-diabetic or lipidemia activating agent and formula I can give simultaneously, perhaps can give one of them earlier, at interval after the short time as several seconds or a few minutes or continue longer interval such as gave another in 10-30 minute.
Because the hydroxamic acid derivatives of formula I strengthens the therapeutic effect of anti-diabetic or lipidemia activating agent synergistically, dosage was low used conventional every day in the conventional therapy when therefore in the method for the invention, the every day of anti-diabetic or lipidemia agent, dosage was than the hydroxamic acid derivatives of giving construction I not.
Use method of the present invention, can prevent the particularly development of following clinical symptoms, perhaps in a single day when developing, they can be affected valuably:
-prediabetes state, for example glucose tolerance or insulin resistance,
-metabolism X-syndrome,
-two types diabetes (IDDM and NIDDM),
-diabetic complication has specifically that retinopathy, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), gestational diabetes (GDM), arterial pressure are too high, dyslipidemia, arteriosclerosis, obesity, cardia ischemia relevant with diabetes or the like.
Therefore, the hydroxamic acid derivatives or its medicinal suitable acid-addition salts that the present invention includes formula I are used to prepare a kind of be used to prevent or treat prediabetes state, metabolism X-syndrome or diabetes and the disorder relevant with top state, be endogenous metabolism disorder, insulin resistance, dyslipidemia, alopecia, alopecia generalisata and/or based on the purposes of the female incretion disorder pharmaceutical composition that produces the masculine sex character advantage, the effect of described pharmaceutical composition enhanced activity agent synergistically, particularly anti-diabetic or lipidemia activating agent.Therefore, contain patient that the medicinal suitable acid-addition salts of the hydroxamic acid derivatives of formula I or its can give to accept anti-diabetic or the treatment of lipidemia activating agent as this pharmaceutical composition of activating agent so that prevention or treatment prediabetes state, metabolism X-syndrome or diabetes and the disorder relevant, i.e. endogenous metabolism disorder, insulin resistance, dyslipidemia, alopecia, alopecia generalisata and/or to produce the female incretion disorder of masculine sex character advantage with last surface state.Containing the medicinal suitable acid-addition salts of the hydroxamic acid derivatives of formula I or its makes the dosage of anti-diabetic or lipidemia activating agent reduce as the pharmaceutical composition of activating agent.When the hydroxamic acid derivatives that contains formula I or its medicinal suitable acid-addition salts, when for example O-(3-piperidino-2 hydroxyls-1-propyl group) nicotinoyl amidoxim or its medicinal suitable acid-addition salts such as its dihydrochloride or a hydrochlorate suffer from diabetes and obtain the patient of regular insulinize as the pharmaceutical composition of activating agent, can reduce insulin dose every day, thereby avoid the progress of insulin resistance.
Claims (3)
1. a synergistic pharmaceutical combination that is used to prevent or treat prediabetes state, metabolism X-syndrome or diabetes and endogenous metabolism disorder, insulin resistance, dyslipidemia, alopecia and/or alopecia generalisata comprises
(a) first pharmaceutical composition, it contains anti-diabetic activity agent and one or more conventional carriers of the salt that is selected from the medicinal suitable acid-addition salts of peroxisome Proliferators-activated receptor γ-agonist and Biguanide derivative or its or forms with medicinal suitable alkali, and
(b) second pharmaceutical composition, it contains O-(3-piperidino-2-hydroxyl-1-propyl group) nicotinoyl amidoxim or its medicinal suitable acid-addition salts and one or more conventional carriers wherein, and the weight ratio of activating agent and O-(3-piperidino-2-hydroxyl-1-propyl group) nicotinoyl amidoxim is (1-100): (100-1).
2. the pharmaceutical composition of claim 1 wherein comprises metformin or its medicinal suitable acid-addition salts as the anti-diabetic activity agent.
3.O-(3-piperidino-2-hydroxyl-1-propyl group) nicotinoyl amidoxim or its medicinal suitable acid-addition salts are used for the purposes of pharmaceutical compositions, described pharmaceutical composition strengthens the effect of the anti-diabetic activity agent that is selected from peroxisome Proliferators-activated receptor γ-agonist and Biguanide derivative synergistically, and described pharmaceutical composition is used for prevention or treatment prediabetes state, metabolism X syndrome or diabetes and endogenous metabolism disorder, insulin resistance, dyslipidemia, alopecia and/or alopecia generalisata.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0102982 | 2001-07-17 | ||
| HU0102982A HU0102982D0 (en) | 2001-07-17 | 2001-07-17 | Synergic pharmaceutical composition |
| HU0202204A HU226244B1 (en) | 2002-07-05 | 2002-07-05 | Pharmaceutical combination for the prophylaxis or treatment of diabetes |
| HUP0202204 | 2002-07-05 |
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| CN200610051370.3A Division CN1840195A (en) | 2001-07-17 | 2002-07-10 | A synergistic pharmaceutical combination for the prevention or treatment of diabetes |
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| EP (1) | EP1408966B1 (en) |
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| CA2582464A1 (en) * | 2004-10-13 | 2006-04-27 | Sanjay Bhanot | Antisense modulation of ptp1b expression |
| US20080108602A1 (en) * | 2006-11-02 | 2008-05-08 | N-Gene Research Laboratories, Inc. | Prevention of obesity in antipsychotic, antidepressant and antiepileptic medication |
| US7763601B2 (en) * | 2006-11-02 | 2010-07-27 | N-Gene Research Laboratories, Inc. | Prevention and treatment of obesity |
| ES2355680T3 (en) * | 2006-11-02 | 2011-03-30 | N-Gene Research Laboratories Inc. | REDUCTION OF OVERWEIGHT OR OBESITY. |
| ES2357983T3 (en) * | 2006-11-02 | 2011-05-04 | N-Gene Research Laboratories Inc. | PHARMACEUTICAL COMPOSITION PRESENTING AN ANTIPSYCHOTIC, ANTIDEPRESSIVE OR ANTIEPILEPTIC ACTIVITY WITH A REDUCED SECONDARY EFFECT. |
| US7753949B2 (en) * | 2007-02-23 | 2010-07-13 | The Trustees Of The University Of Pennsylvania | Valve prosthesis systems and methods |
| EP2185138B1 (en) | 2007-07-19 | 2016-09-07 | Takeda Pharmaceutical Company Limited | Solid preparation comprising alogliptin and metformin hydrochloride |
| CA2707484C (en) | 2007-12-04 | 2021-08-10 | Remedy Pharmaceuticals, Inc. | Improved formulations and methods for lyophilization and lyophilates provided thereby |
| WO2009074835A1 (en) * | 2007-12-10 | 2009-06-18 | N-Gene Research Laboratories Inc. | Dose reduction of a cannabinoid cb1 receptor antagonist in the treatment of overweight or obesity |
| AU2012242642A1 (en) | 2011-04-13 | 2013-05-02 | Ionis Pharmaceuticals, Inc. | Antisense modulation of PTP1B expression |
| HUP1100444A2 (en) | 2011-08-17 | 2013-02-28 | Pharma Gene Sa | Pharmaceutical composition |
| HUP1100445A2 (en) | 2011-08-17 | 2013-02-28 | Pharma Gene Sa | Pharmaceutical composition |
| CN105476995A (en) * | 2015-12-23 | 2016-04-13 | 青岛海之源智能技术有限公司 | Metformin-acipimox compound sustained-release capsule and preparing method |
| KR20240033119A (en) | 2017-06-30 | 2024-03-12 | 더 리전트 오브 더 유니버시티 오브 캘리포니아 | Compositions and methods of modulation of hair growth |
| HUP1800298A1 (en) | 2018-08-30 | 2020-05-28 | N Gene Res Laboratories Inc | Combination of beta blocker and hydroximic acid derivative with reduced side effects |
| US20210369689A1 (en) * | 2020-05-27 | 2021-12-02 | Corcept Therapeutics Incorporated | Concomitant administration of glucocorticoid receptor modulator relacorilant and cyp2c9 substrates |
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| US4308399A (en) * | 1977-08-30 | 1981-12-29 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | O-(3-Amino-2-hydroxy-propyl)-amidoxime derivatives, process for the preparation thereof and pharmaceutical compositions containing same |
| HU207988B (en) * | 1988-10-20 | 1993-07-28 | Biorex Kutato Fejlesztoe Kft | Process for producing halogenides of o-/3-amino-2-hydroxy-propyl/hydroximic acid and pharmaceutical compositions containing them as active components |
| US5190970A (en) * | 1990-10-19 | 1993-03-02 | E. R. Squibb & Sons, Inc. | Method for preventing onset of or treating Type II diabetes employing a cholesterol lowering drug alone or in combination with an ace inhibitor |
| US6011049A (en) * | 1997-02-19 | 2000-01-04 | Warner-Lambert Company | Combinations for diabetes |
| US6291495B1 (en) * | 1997-02-24 | 2001-09-18 | Robert B. Rieveley | Method and composition for the treatment of diabetes |
| US6153632A (en) * | 1997-02-24 | 2000-11-28 | Rieveley; Robert B. | Method and composition for the treatment of diabetes |
| US6121278A (en) * | 1997-09-03 | 2000-09-19 | Guilford Pharmaceuticals, Inc. | Di-n-heterocyclic compounds, methods, and compositions for inhibiting parp activity |
| WO2000007580A2 (en) * | 1998-08-03 | 2000-02-17 | N-Gene Kutató Kft. | Pharmaceutical compositions against autoimmune diseases |
| UA65635C2 (en) | 1998-09-03 | 2004-04-15 | Н-Гене Кутато Кфт. | UNSATURATED HYDROXIMIC ACID DERIVATIVES HAVING PROPERTIES OF NAD<sup>+-ADP-RIBOSYLTRANSFERASE INHIBITORS |
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